Open AccessHLA-Associated Alterations in Replication Capacity of Chimeric NL4-3 Viruses Carrying gag-protease from Elite Controllers of Human Immunodeficiency Virus Type 1
Author(s) -
Toshiyuki Miura,
Mark A. Brockman,
Zabrina L. Brumme,
Chanson J. Brumme,
Florencia Pereyra,
Alicja Trocha,
Brian L. Block,
Arne Schneidewind,
Todd M. Allen,
David Heckerman,
Bruce D. Walker
Publication year - 2009
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.01471-08
Subject(s) - biology , virology , virus , viral replication , lentivirus , human leukocyte antigen , allele , ctl* , microbiology and biotechnology , genetics , cytotoxic t cell , gene , antigen , viral disease , in vitro
Human immunodeficiency virus type 1 (HIV-1)-infected persons who maintain plasma viral loads of <50 copies RNA/ml without treatment have been termed elite controllers (EC). Factors contributing to durable control of HIV in EC are unknown, but an HLA-dependent mechanism is suggested by overrepresentation of “protective” class I alleles, such as B*27, B*51, and B*57. Here we investigated the relative replication capacity of viruses (VRC) obtained from EC (n = 54) compared to those from chronic progressors (CP;n = 41) by constructing chimeric viruses using patient-derivedgag-protease sequences amplified from plasma HIV RNA and inserted into an NL4-3 backbone. The chimeric viruses generated from EC displayed lower VRC than did viruses from CP (P < 0.0001). HLA-B*57 was associated with lower VRC (P = 0.0002) than were other alleles in both EC and CP groups. Chimeric viruses from B*57+ EC (n = 18) demonstrated lower VRC than did viruses from B*57+ CP (n = 8,P = 0.0245). Differences in VRC between EC and CP were also observed for viruses obtained from individuals expressing no described “protective” alleles (P = 0.0065). Intriguingly, two common HLA alleles, A*02 and B*07, were associated with higher VRC (P = 0.0140 and 0.0097, respectively), and there was no difference in VRC between EC and CP sharing these common HLA alleles. These findings indicate that cytotoxic T-lymphocyte (CTL) selection pressure ongag-protease alters VRC, and HIV-specific CTLs inducing escape mutations with fitness costs in this region may be important for strict viremia control in EC of HIV.